My immediate career goals are to gain the knowledge and skills to transition from postdoctoral fellow to an independent investigator. My long-term career goals are to carve a scientific career out of my interests in obesity, insulin resistance, and their associated co-morbidities-of which sleep apnea is of particular consideration. My research career development plan is to acquire expertise in a translational approach to clinical questions. This pathway will enable me to apply and integrate a variety of experimental techniques, molecular biological concepts, and clinical skills. Proficiency in these areas will be achieved by clinical and benchwork training, and complemented by formal didactics through the graduate program in Epidemiology, seminars and conferences, and feedback from an Advisory Committee of senior investigators. Representing diverse disciplines in the medical sciences, this Committee will help oversee my maturation into an independent clinician-scientist. The epidemic of overweight and obesity in the United States has been accompanied by the rising prevalence of its associated co-morbidities. Adiposity is a well-established risk factor for sleep-related breathing disorders as well as type 2 diabetes (T2DM). That these conditions are associated with significant risk of cardiovascular disease renders them important targets of primary and secondary prevention. Recently, attention has shifted to evaluating the relationship between obstructive sleep apnea (OSA) and T2DM. Population-based studies have demonstrated that the frequency of OSA is increased among individuals with T2DM, and conversely, that the prevalence of glycemic disturbances is increased among patients with OSA. Multiple pathophysiologic mechanisms linking OSA with insulin resistance have been postulated. While obesity may be one of these mechanisms, extant data suggest that obesity, per se, cannot fully account for this relationship, and other factors related to insulin resistance may be implicated. In this context, the biological role that apelin, a novel bioactive peptide secreted by adipocytes, is of interest. Apelin has been shown to play a role in regulation of insulin action, and recent data suggest that it may also modulate respiratory control. These observations provide the basis for a heretofore unsuspected, and potentially important, link among adiposity, insulin resistance, and OSA. Furthermore, while most investigations have focused on the development of T2DM as a consequence of OSA, generally overlooked is the possibility that OSA may be a consequence of insulin resistance and/ or T2DM. These uncertainties have led to this proposal with the following aims: (1) To perform a cross-sectional evaluation of insulin resistance in overweight/ moderately obese, non-diabetic individuals diagnosed with OSA. These individuals will be compared to BMI-matched control subjects without a diagnosis of OSA. Direct quantification of insulin-mediated glucose uptake will ascertain whether individuals with OSA indeed represent a population at increased risk for insulin resistance as compared to the general population. (2) To evaluate the extent to which insulin sensitivity and OSA modulate apelin. To test this interaction, plasma apelin levels will be compared among insulin resistant and insulin sensitive subjects with OSA, and BMI-matched insulin resistant and insulin sensitive control subjects. (3) To compare the effects of CPAP plus pioglitazone versus CPAP plus placebo on insulin resistance, OSA symptoms, and apelin in overweight, insulin resistant subjects with OSA. Insulin resistant subjects with untreated OSA will be randomized to either group, with the goal to assess whether pioglitazone augments the clinical benefit of CPAP therapy on insulin sensitivity, leads to reduction in symptoms and severity of OSA, and alters plasma and adipose tissue apelin levels. This proposal will lay the groundwork for characterizing novel mechanisms underlying the relationships among adiposity, OSA, and insulin resistance. PUBLIC HEALTH RELEVANCE: Obstructive sleep apnea and type 2 diabetes confer increasing economic, social, and public health burdens in the United States. That these diseases appear to co-exist renders investigation into their shared pathophysiology even more urgent. A therapeutic approach testing putative mechanisms linking adiposity, sleep apnea, and insulin resistance may lead to novel strategies in prevention and intervention.